We wished to determine the influence of the apolipoprotein E (Apo-E) genotype on the loss of high affinity nicotinic acetylcholine receptor (nAChR) binding in Alzheimer's disease (AD). The interaction between ε4 allele gene dose and cholinergic loss in AD remains controversial. We have demonstrated that nicotinic binding is significantly lost in AD. Tissue from the midfrontal (MF) cortex of 7 subjects with no ε4 allele copies (ε−/ε−) (mean death age 75.1 ± 10.4 years) was compared to MF cortex of 14 subjects heterozygous for the ε4 allele (ε4/ε−) (mean death age 81.4 ± 7.3 years) and MF cortex of 10 subjects homozygous for the ε4 allele (ε4/ε4) (mean death age 79.6 ± 5.0 years). All subjects were autopsy confirmed AD (using NIA and CERAD criteria) and met NINCDS-ADRDA clinical criteria for probable or possible AD. Nicotine AChR binding was assayed using the high affinity nicotinic agonist ³H-epibatidine ([³H]-Epi). Apo-E genotype was determined in blood samples or in post-mortem tissue. The mean age at death was not significantly different among the groups (p = 0.19). There was no difference in mean [³H]-Epi total binding among the three groups (6.7 ± 4.6, 6.1 ± 2.4, and 6.0 ± 1.0 fmol/mg protein for ε−/ε−, ε4/ε−, and ε4/ε4 respectively. We conclude that the presence or absence of the Apo-E4 genotype does not influence the loss of high affinity nAChR in AD.